Cesium carbonate → Methyl 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoro-2-(isoquinoline 4-ylamino)nicotinate

HRID 2406763Notes

Reaction equation

HRID 2406763 reaction equation
Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH2:60][C:61]1[N:70]=[C:69]([NH:71][C@@H:72]2[CH2:77][CH2:76][CH2:75][CH2:74][C@@H:73]2[NH:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[C:68]([F:86])=[CH:67][C:62]=1[C:63]([O:65][CH3:66])=[O:64]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.O1CCOCC1>[C:82]([O:81][C:79]([NH:78][C@H:73]1[CH2:74][CH2:75][CH2:76][CH2:77][C@H:72]1[NH:71][C:69]1[C:68]([F:86])=[CH:67][C:62]([C:63]([O:65][CH3:66])=[O:64])=[C:61]([NH:60][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][CH:3]=2)[N:70]=1)=[O:80])([CH3:85])([CH3:83])[CH3:84]

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 737434-BromoisoquinolineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86683887Methyl2-amino-6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoronicotinate

Product 1

HCID 86683886Methyl 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoro-2-(isoquinoline 4-ylamino)nicotinateYield 72.2%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

4-bromoisoquinoline (65 mg), cesium carbonate (170 mg), Pd2(dba)3 (29 mg), and Xantphos (36 mg) were added to a 1,4-dioxane (2.1 ml) solution containing methyl 2-amino-6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoronicotinate (80 mg), followed by stirring at 100° C. for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. Insoluble matter was removed by filtration, and the filter cake was washed with water and ethyl acetate. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 to 1:2), diisopropylether was added, solid matter was collected by filtration, and a light yellow solid of methyl 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoro-2-(isoquinoline 4-ylamino)nicotinate (77 mg) was obtained.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customInsoluble matter was removed by filtration
  3. washthe filter cake was washed with water and ethyl acetate
  4. customThe organic layer was collected
  5. washwashed with saturated saline
  6. dry with materialdried over anhydrous magnesium sulfate
  7. distillationthe solvent was distilled away under reduced pressure
  8. customThe obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 to 1:2), diisopropylether
  9. additionwas added
  10. filtrationsolid matter was collected by filtration

Sources & evidence

ORD record
ord-4ab1b727344b4747a91fd9fc414a5a78
Source dataset
uspto-grants-2014_08
Patent number
US08809371B2

Reaction notes

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